Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody–Drug Conjugates,Journal of Medicinal Chemistry

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Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody–Drug Conjugates
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-12-30 , DOI: 10.1021/acs.jmedchem.2c01812
Wei Shi _{1,

2} , Jianxin Zhang _{1,

3} , Liya Liu _{1,

4} , Wanzhen Li _{1,

3} , Zhi Liu ₃ , Anni Ren ₂ , Jie Wang ₂ , Caihong Tang ₁ , Yang Yang ₂ , Dandan Xu ₂ , Qianqian Huang ₂ , Yongqin Wang ₂ , Caili Luo ₂ , Wei Huang _{1,

2,

3,

4,

5} , Feng Tang _{1,

2,

4}

Affiliation

The inadequate understanding of the structure–activity relationship (SAR) of glycosite-specific antibody–drug conjugates (ADCs) hinders its design and development. Herein, we revealed the systemic SAR and structure–toxicity relationship (STR) of gsADCs by constructing 50 gsADC structures bearing three glycan subtypes and diverse linker-drug combinations. According to the results, extra hydrophilic linkers are indispensable for the intact glycan-based gsADCs to achieve better in vivo efficacy. Meanwhile, the gsADCs that conjugate linker-drug complexes onto the terminal sialic acid are more stable and potent than the ones conjugated onto the terminal galactose in vivo. Notably, the LacNAc-based gsADCs, which shortened the spacer and located the linker-drug more inside the immunoglobulin class G (IgG) Fc cavity, showed excellent hydrophilicity, in vivo activity, pharmacokinetics, and safety. Conclusively, we found that hiding the linker-toxin into the Fc cavity can significantly enhance the therapeutic index of LacNAc-based gsADCs, which will benefit the further design of ADCs with optimal druggability.

中文翻译：

将有效载荷隐藏在 IgG Fc 腔内可显着提高抗体-药物偶联物的治疗指数

对糖苷特异性抗体-药物偶联物 (ADC) 的构效关系 (SAR) 的了解不足阻碍了其设计和开发。在此，我们通过构建具有三种聚糖亚型和不同接头-药物组合的 50 个 gsADC 结构，揭示了 gsADC 的全身 SAR 和结构-毒性关系 (STR)。根据结果，额外的亲水性接头对于完整的基于聚糖的 gsADC 实现更好的体内功效是必不可少的。同时，在体内将接头-药物复合物缀合到末端唾液酸上的 gsADC 比缀合到末端半乳糖上的 gsADC 更稳定、更有效. 值得注意的是，基于 LacNAc 的 gsADC 缩短了间隔区并将接头药物更多地定位在 G 类免疫球蛋白 (IgG) Fc 腔内，显示出出色的亲水性、体内活性、药代动力学和安全性。最后，我们发现将接头毒素隐藏到 Fc 腔中可以显着提高基于 LacNAc 的 gsADC 的治疗指数，这将有利于进一步设计具有最佳成药性的 ADC。

更新日期：2022-12-30

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